Antitumoral Activity of Cecropia Pachystachya Leaves Extract in Vitro and in Vivo Model of Rat Glioma: Brain and Blood Effects.

The aim of this study was to investigate the antiglioma effect of Cecropia pachystachya Trécul (CEC) leaves extract against C6 and U87 glioblastoma (GB) cells and in a rat preclinical GB model. The CEC extract reduced in vitro cell viability and biomass. In vivo, the extract decreased the tumor volume approximately 62%, without inducing systemic toxicity. The deficit in locomotion and memory and an anxiolytic-like behaviors induced in the GB model were minimized by CEC. The extract decreased the levels of reactive oxygen species, nitrites and thiobarbituric acid reactive substances and increased the activity of antioxidant enzymes in platelets, sera and brains of GB animals. The activity of NTPDases, 5'-nucleotidase and adenosine deaminase (ADA) was evaluated in lymphocytes, platelets and serum. In platelets, ATP and AMP hydrolysis was reduced and hydrolysis of ADP and the activity of ADA were increased in the control, while in CEC-treated animals no alteration in the hydrolysis of ADP was detected. In serum, the reduction in ATP hydrolysis was reversed by CEC. In lymphocytes, the increase in the hydrolysis of ATP, ADP and in the activity of ADA observed in GB model was altered by CEC administration. The observed increase in IL-6 and decrease in IL-10 levels in the serum of GB animals was reversed by CEC. These results demonstrate that CEC extract is a potential complementary treatment to GB, decreasing the tumor size, while modulating aspects of redox and purinergic systems.

Chemical hypermethioninemia in young mice: oxidative damage and reduction of antioxidant enzyme activity in brain, kidney, and liver.

High levels of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), found in hypermethioninemia, can be detrimental to the body; however, the underlying mechanisms are still uncertain. Using a recently standardized protocol, the aim of this study was to investigate the effects of chronic administration of Met and/or MetO on parameters of oxidative damage in the total brain, liver, and kidney of young mice. Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. Results showed that Met and/or MetO caused an increase in reactive oxygen species (ROS) and lipoperoxidation, along with a reduction of superoxide dismutase (SOD) and catalase (CAT) activities in the brain. In the liver, Met and/or MetO enhanced ROS and nitrite levels, and reduced SOD, CAT, and delta aminolevulinic dehydratase activities. The effects on the kidney were an increase in ROS production and SOD activity, and a reduction in thiol content and CAT activity. These data demonstrated the contribution of redox imbalance to the systemic changes found in patients with hypermethioninemia. In conclusion, our findings may help future studies to better understand the pathophysiological mechanisms of hypermethioninemia as well as contribute to the search for new therapeutic agents for this pathology.

Blueberry Extract Modulates Brain Enzymes Activities and Reduces Neuroinflammation: Promising Effect on Lipopolysaccharide-Induced Depressive-Like Behavior.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na+/K+-ATPase, monoamine oxidase-A (MAO-A), and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus of mice subject to lipopolysaccharide (LPS)-induced depressive-like behavior. We also analyzed the interaction between anthocyanins and indoleamine 2 3-dioxygenase (IDO). Male Swiss mice (60-day-old) received vehicle, fluoxetine (20 mg/kg), or blueberry extract (100 or 200 mg/kg) intragastrically for 7 days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, the mice were subjected to behavioral tests. Both fluoxetine and blueberry extract (200 mg/kg) decreased the immobility time in the forced swim test, without affecting locomotor activity. Fluoxetine attenuated the decrease of Na+/K+-ATPase in the cerebral cortex, while blueberry extract promoted this same effect in the hippocampus. Additionally, fluoxetine and blueberry extract attenuated the decrease in the activity of MAO-A in the hippocampus. Blueberry extract (200 mg/kg) also prevented LPS-induced increase in AChE activity in the hippocampus as well as LPS upregulation of relative mRNA expression of tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-10 in the cerebral cortex. Molecular docking analysis revealed binding sites for malvidin 3-galactoside (- 7.8 kcal/mol) and malvidin 3-glucoside (- 7.9 kcal/mol) residues with IDO. Taken together, these results indicate that blueberry extract improved depression-like behavior and attenuated the neurochemical and molecular changes in the brains of mice challenged with LPS.

Impact of gallic acid on tumor suppression: Modulation of redox homeostasis and purinergic response in in vitro and a preclinical glioblastoma model.

Glioblastoma (GBM) is the deadliest primary brain tumor in adults due to the high rate of relapse with current treatment. Therefore, the search for therapeutic alternatives is urgent. Gallic acid (GA), a potent natural antioxidant, has antitumor and modulatory actions on purinergic signaling. In this study, we investigated the cytotoxic effects of GA on the rat GBM (C6) cell line and on astrocyte culture and analyzed its role in regulating oxidative stress and purinergic enzymes involved in GBM proliferation. Cells were exposed to GA from 50 to 400 µM for 24 and/or 48 h. Next, the effect of GA was evaluated in the preclinical model of GBM. Wistar rats were treated with 50 or 100 mg/kg of GA for 15 days, and cerebral and systemic redox status and degradation of adenine nucleotides and nucleosides in circulating platelets, lymphocytes, and serum were evaluated. Our results demonstrated that GA has selective anti-glioma activity in vitro, without inducing cytotoxicity in astrocyte. Furthermore, GA prevented oxidative stress and changes in the hydrolysis of nucleotides in GBM cells. The anti-glioma effect was also observed in vivo, as GA reduced tumor volume by 90%. Interestingly, GA decreased the oxidative damage induced by a tumor in the brain, serum, and platelets, and, also prevented changes in the degradation of nucleotides and nucleosides in lymphocytes, platelets, and serum. These results indicate, for the first time, the therapeutic potential of GA in a preclinical model of GBM, whose effects may be related to its role in redox and purinergic modulation.

LPS-induced impairment of Na+/K+-ATPase activity: ameliorative effect of tannic acid in mice.

Acetylcholine is an excitatory neurotransmitter that modulates synaptic plasticity and communication, and it is essential for learning and memory processes. This neurotransmitter is hydrolyzed by acetylcholinesterase (AChE), which plays other cellular roles in processes such as inflammation and oxidative stress. Ion pumps, such as Na+/K+-ATPase and Ca2+-ATPase, are highly expressed channels that derive energy for their functions from ATP hydrolysis. Impairment of the cholinergic system and ion pumps is associated with neuropsychiatric diseases. Major depressive disorder (MDD) is an example of a complex disease with high morbidity and a heterogenous etiology. Polyphenols have been investigated for their therapeutic effects, and tannic acid (TA) has been reported to show neuroprotective and antidepressant-like activities. Animal models of depression-like behavior, such as lipopolysaccharide (LPS)-induced models of depression, are useful for investigating the pathophysiology of MDD. In this context, effects of TA were evaluated in an LPS-induced mouse model of depression-like behavior. Animals received TA for 7 days, and on the last day of treatment, LPS (830 µg/kg) was administered intraperitoneally. In vitro exposure of healthy brain to TA decreased the AChE activity. Additionally, this enzyme activity was decreased in cerebral cortex of LPS-treated mice. LPS injection increased the activity of Ca2+-ATPase in the cerebral cortex but decreased the enzyme activity in the hippocampus. LPS administration decreased Na+/K+-ATPase activity in the cerebral cortex, hippocampus, and striatum; however, TA administration prevented these changes. In conclusion, tannins may affect Na+/K+-ATPase and Ca2+-ATPase activities, which is interesting in the context of MDD.

Thiazolidine-2,4-dione derivative exhibits antitumoral effect and reverts behavioral and metabolic changes in a model of glioblastoma.

The aim of the present study was to evaluate the anti-glioma activity of 3-(4-fluorobenzyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (AV23) in a preclinical model of glioblastoma, as well as behavioral parameters and toxicological profile. The implantation of C6 cells in the left striatum of male Wistar rats was performed by stereotaxic surgery. After recovery, animals were treated with vehicle (canola oil) or AV23 (10 mg/kg/day) intragastrically for 15 days. It was found that AV23 reduced tumor volume by 90%. Serum biochemical parameters such as triglycerides, cholesterol, HDL-cholesterol, LDL-cholesterol, albumin, aspartate aminotransferase, urea, creatinine and total proteins were not changed; however, there was a slight increase in alanine aminotransferase. The compound AV23 reverted the hypoglycemia and the reduction in body weight caused by glioblastoma. Additionally, AV23 was able to revert the reduction of locomotion caused by the tumor implantation. Therefore, the compound AV23 can be considered a promising candidate in the treatment of glioblastoma.

Tannic Acid Attenuates Peripheral and Brain Changes in a Preclinical Rat Model of Glioblastoma by Modulating Oxidative Stress and Purinergic Signaling.

Glioblastoma (GB) is a highly aggressive and invasive brain tumor; its treatment remains palliative. Tannic acid (TA) is a polyphenol widely found in foods and possesses antitumor and neuroprotective activities. This study aimed to investigate the effect of TA on oxidative stress parameters and the activity of ectonucleotidases in the serum, platelets, and lymphocytes and/or in the brain of rats with preclinical GB. Rats with GB were treated intragastrically with TA (50 mg/kg/day) for 15 days or with a vehicle. In the platelets of the animals with glioma, the adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolysis and the catalase (CAT) activity decreased. Besides, the adenosine diphosphate (ADP) hydrolysis, adenosine (Ado) deamination, and the reactive oxygen species (ROS) and nitrite levels were increased in glioma animals; however, TA reversed ROS and nitrite levels and AMP hydrolysis alterations. In lymphocytes from animals with glioma, the ATP and ADP hydrolysis, as well as Ado deamination were increased; TA treatment countered this increase. In the brain of the animals with glioma, the ROS, nitrite, and thiobarbituric acid reactive substance (TBARS) levels increased and the thiol (SH) levels and CAT and superoxide dismutase (SOD) activities were decreased; TA treatment decreased the ROS and TBARS levels and restored the SOD activity. In the serum of the animals with glioma, the ATP hydrolysis decreased; TA treatment restored this parameter. Additionally, the ROS levels increased and the SH and SOD activity decreased by glioma implant; TA treatment enhanced nitrite levels and reversed SOD activity. Altogether, our results suggest that TA is an important target in the treatment of GB, as it modulates purinergic and redox systems.

Effect of blueberry extract on energetic metabolism, levels of brain-derived neurotrophic factor, and Ca2+-ATPase activity in the hippocampus and cerebral cortex of rats submitted to ketamine-induced mania-like behavior.

Bipolar disorder (BD) is a psychiatric disease characterized by mood episodes. Blueberry is rich in bioactive compounds and shows excellent therapeutic potential against chronic diseases. The aim of this study was to evaluate the effects of blueberry extract on behavior, energetic metabolism, Ca2+-ATPase activity, and levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex and hippocampus of rats submitted to an animal model of mania induced by ketamine. Vehicle, lithium (45 mg/kg, twice a day), or blueberry extract (200 mg/kg), was orally administered to Wistar rats for 14 days. Ketamine (25 mg/kg) or vehicle was administered intraperitoneally, once a day, between the 8th and 14th day. On the 15th day, animals received ketamine or vehicle and were subjected to the open field test. Our results demonstrated that the administration of lithium and blueberry extract prevented ketamine-induced hyperlocomotion (P < 0.01). Blueberry extract attenuated the ketamine-induced reduction in the activity of complex I in the cerebral cortex (P < 0.05). Additionally, the administration of ketamine reduced the activities of complexes I and IV (P < 0.05) and citrate synthase in the hippocampus (P < 0.01). However, blueberry extract attenuated the inhibition in the activity of complex IV (P < 0.01). Furthermore, ketamine reduced the Ca2+-ATPase activity in the cerebral cortex and hippocampus (P < 0.05); however, blueberry extract prevented the change in the cerebral cortex (P < 0.05). There were no significant alterations in the levels of BDNF (P > 0.05). In conclusion, this suggested that the blueberry extract can serve as a potential therapeutic strategy for studies searching for novel therapeutic alternatives for BD patients.

Blueberry extract as a potential pharmacological tool for preventing depressive-like behavior and neurochemical dysfunctions in mice exposed to lipopolysaccharide.

OBJECTIVE: Major depressive disorder is a debilitating and recurrent psychiatric disorder. Blueberries have several biological properties, including neuroprotective effects, through antioxidant and anti-inflammatory actions. The aim of this study was to evaluate the effect of blueberry extract on depressive-like behavior and lipopolysaccharide (LPS)-induced neurochemical changes. METHODS: Mice were pretreated with vehicle, fluoxetine (20 mg/kg) or blueberry extract (100 or 200 mg/kg) intragastrically for seven days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, mice were submitted to behavioral tests. Oxidative stress and neuroinflammatory parameters were evaluated in the cerebral cortex, hippocampus, and striatum. RESULTS: Our data showed that blueberry extract or fluoxetine treatment protected against LPS-induced depressive-like behavior in tail suspension and splash tests (P < 0.05), without changes in locomotor activity (P > 0.05). LPS induced an increase in the levels of reactive oxygen species (P < 0.001), nitrite (P < 0.05) and thiobarbituric acid reactive substances (P < 0.01), as well as a reduction in total sulfhydryl content (P < 0.05) and catalase activity (P < 0.05) in brain structures; blueberry extract restored these alterations (P < 0.05). In addition, blueberry extract attenuated the increase in tumor necrosis factor-alpha (TNF-α) levels induced by LPS administration (P < 0.05). CONCLUSION: This study showed that blueberry extract exerted antidepressant-like effects, protected the brain against oxidative damage, and modulated TNF-α levels induced by LPS.

Protective Effects of Inosine on Memory Consolidation in a Rat Model of Scopolamine-Induced Cognitive Impairment: Involvement of Cholinergic Signaling, Redox Status, and Ion Pump Activities.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.

Selective in vitro anticancer effect of blueberry extract (Vaccinium virgatum) against C6 rat glioma: exploring their redox status.

The aim of this study was to investigate the anticancer potential of blueberry extract (Vaccinium virgatum) against a C6 rat glioma lineage. Cultures of the C6 cells were exposed to blueberry extract at concentrations of 50 to 600 µg/mL for 12, 24, 48, or 72 h and then evaluated for cell viability, proliferation, migration, colony formation and oxidative stress. We also evaluated the effects of blueberry extract on primary rat cortical astrocytes. Our results show that treatment with blueberry extract did not alter the viability or proliferation of normal primary astrocytes but it did significantly reduce the viability in 21.54 % after 48 h and proliferation in 8.59 % after 24 h of C6 cells at 200 µg/mL. We also observed a reduction in the size of the colonies of 29.99 % at 100 µg/mL when compared to the control cells and cell migration was also reduced at 50 µg/mL. After 72 h, there was a reduction in the reactive oxygen species levels ranging from 46.26 to 34.73 %, in addition to a 380.2 % increase in total thiol content. Superoxide dismutase, catalase, and glutathione S-transferase activities were also enhanced when compared to the control. Taken together this data suggests that blueberry extract exerts some selective anticancer activity in C6 glioma cells.

Effect of blueberry (Vaccinium virgatum) extract on depressive-like behavior and metabolic serum alterations in lipopolysaccharide-challenged mice.

In the present study, we aimed to investigate the protective effect of blueberry extract on behavioral, biochemical, and morphological changes in an experimental model of lipopolysaccharide (LPS)-induced depressive behavior. Male Swiss mice were pretreated with the vehicle, fluoxetine (20 mg/kg), or Vaccinium virgatum extract (100 mg/kg and 200 mg/kg) for seven days. On day 7, the animals were administered an LPS injection (0.83 mg/kg) or vehicle. Pretreatment with blueberry extract prevented LPS-induced depressive-like behavior. Moreover, LPS increased serum levels of total cholesterol; however, V. virgatum did not prevent the increase in total cholesterol levels. Furthermore, the extract prevented the LPS-induced elevation in serum reactive oxygen species. Also, V. virgatum extract increased the HDL cholesterol levels. Additionally, this extract prevented the LPS-induced decrease in glucose levels and serum adenosine deaminase activity. Collectively, V. virgatum extract has a potential protective effect against changes similar to those observed in patients with depression. PRACTICAL APPLICATIONS: Vaccinium virgatum, popularly known as blueberry, has been effective in preventing or treating neuropsychiatric diseases owing to its antioxidant, anti-inflammatory, and neuroprotective properties. Fluoxetine is a known drug used to treat depression; however, its adverse effects result in therapeutic non-adherence. Thus, the search for new natural compounds possessing antidepressant activities while lacking adverse effects is crucial for identifying novel therapeutic alternatives against depression.

Therapeutic approaches employing natural compounds and derivatives for treating bipolar disorder: emphasis on experimental models of the manic phase.

Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.

The Protective Action of Rubus sp. Fruit Extract Against Oxidative Damage in Mice Exposed to Lipopolysaccharide.

Neuroinflammation is an event that occurs in several pathologies of brain. Rubus sp. (blackberry) is a powerful antioxidant fruit, and its extract has neuroprotective activity. The aim of this study was to investigate the blackberry extract properties on lipopolysaccharide (LPS)-induced neuroinflammation, in relation to oxidative parameters and acetylcholinesterase activity in the brain structures of mice. We also investigated interleukin-10 levels in serum. Mice were submitted to Rubus sp. extract treatment once daily for 14 days. On the fifteenth day, LPS was injected in a single dose. LPS induced oxidative brain damage and the blackberry extract demonstrated preventive effects in LPS-challenged mice. LPS administration increased reactive oxygen species levels in the cerebral cortex and striatum, as well as lipid peroxidation in the cerebral cortex. However, the blackberry extract prevented all these parameters. Furthermore, LPS decreased thiol content in the striatum and hippocampus, while a neuroprotective effect of blackberry extract treatment was observed in relation to this parameter. The blackberry extract also prevented a decrease in catalase activity in all the brain structures and of superoxide dismutase in the striatum. An increase in acetylcholinesterase activity was detected in the cerebral cortex in the LPS group, but this activity was decreased in the Rubus sp. extract group. Serum IL-10 levels were reduced by LPS, and the extract was not able to prevent this change. Finally, we observed an antioxidant effect of blackberry extract in LPS-challenged mice suggesting that this anthocyanin-rich extract could be considered as a potential nutritional therapeutic agent for preventive damage associated with neuroinflammation.

Acute hypermethioninemia impairs redox homeostasis and acetylcholinesterase activity in the hippocampus, striatum, and cerebellum of young rats.

Hypermethioninemia is characterized by high plasma concentrations of methionine (Met) and its metabolites, such as methionine sulfoxide (MetO), and neurological changes, such as cerebral edema and cognitive deficits. The aim of this study was to analyze the redox status and acetylcholinesterase (AChE) activity in the hippocampus, striatum, and cerebellum of young Wistar rats subjected to an acute hypermethioninemia protocol. The animals received, by subcutaneous injection, a single dose of Met (0.4 g/kg), MetO (0.1 g/kg), and Met + MetO, and 1 or 3 hr after administration, the animals were euthanatized for brain structure obtaining. In the hippocampus, an increase in lipid peroxidation and glutathione peroxidase (GPx) activity was observed at 1 hr in the MetO and Met + MetO groups, and a reduction in the superoxide dismutase activity was found in the Met + MetO group. Met and/or MetO induced a decrease in the thiol content and GPx activity and enhanced the lipid peroxidation at 3 hr. In the striatum, a reduction in the thiol content and GPx activity, an increase in lipid peroxidation, and AChE activity were induced by Met and/or MetO at 1 or 3 hr. Additionally, in the cerebellum, an increase in the AChE in the MetO and Met + MetO groups 1 hr after administration was observed. These data help to better understand the pathophysiological mechanisms that underlie the neurological changes found in hypermethioninemia patients.

Gallic acid protects cerebral cortex, hippocampus, and striatum against oxidative damage and cholinergic dysfunction in an experimental model of manic-like behavior: Comparison with lithium effects.

Bipolar disorder is characterized by episodes of depression and mania, and oxidative stress has been associated with the observed neurochemical changes in this disease. We evaluated the effects of gallic acid on hyperlocomotion, acetylcholinesterase activity, and oxidative stress in an animal model of ketamine-induced mania. Rats were pretreated orally with vehicle, gallic acid (50 or 100 mg/kg), or lithium (45 mg/kg twice a day) for 14 days. Between days 8 and 14, the animals also received ketamine (25 mg/kg) or saline daily. On the 15th day, hyperlocomotion was assessed, following which the animals were euthanized, and brains were collected. Results showed that ketamine-induced hyperlocomotion and caused oxidative damage by increasing reactive oxygen species levels, lipid peroxidation, and nitrite levels, and decreasing the total thiol content and the activities of catalase, superoxide dismutase, and glutathione peroxidase in the brain. Pretreatment with gallic acid and lithium prevented hyperlocomotion and brain oxidative damage. Further, ketamine increased the acetylcholinesterase activity in the hippocampus and striatum, whereas gallic acid and lithium ameliorated this alteration. Thus, gallic acid may provide effective protection against manic-like behavior by reducing oxidative stress and preventing cholinergic signaling dysfunction in the brain regions involved in emotion regulation.

Ameliorative effect of tannic acid on hypermethioninemia-induced oxidative and nitrosative damage in rats: biochemical-based evidences in liver, kidney, brain, and serum.

We investigated the ability of tannic acid (TA) to prevent oxidative and nitrosative damage in the brain, liver, kidney, and serum of a rat model of acute hypermethioninemia. Young Wistar rats were divided into four groups: I (control), II (TA 30 mg/kg), III (methionine (Met) 0.4 g/kg + methionine sulfoxide (MetO) 0.1 g/kg), and IV (TA/Met + MetO). Rats in groups II and IV received TA orally for seven days, and rats of groups I and III received an equal volume of water. After pretreatment with TA, rats from groups II and IV received a single subcutaneous injection of Met + MetO, and were euthanized 3 h afterwards. In specific brain structures and the kidneys, we observed that Met + MetO led to increased reactive oxygen species (ROS), nitrite, and lipid peroxidation levels, followed by a reduction in thiol content and antioxidant enzyme activity. On the other hand, pretreatment with TA prevented both oxidative and nitrosative damage. In the serum, Met + MetO caused a decrease in the activity of antioxidant enzymes, which was again prevented by TA pretreatment. In contrast, in the liver, there was a reduction in ROS levels and an increase in total thiol content, which was accompanied by a reduction in catalase and superoxide dismutase activities in the Met + MetO group, and pretreatment with TA was able to prevent only the reduction in catalase activity. Conclusively, pretreatment with TA has proven effective in preventing oxidative and nitrosative changes caused by the administration of Met + MetO, and may thus represent an adjunctive therapeutic approach for treatment of hypermethioninemia.

Antidepressant Effect and Modulation of the Redox System Mediated by Tannic Acid on Lipopolysaccharide-Induced Depressive and Inflammatory Changes in Mice.

Depression is an emotional disorder that causes mental and physical changes, and has limited pharmacotherapy. Tannic acid (TA) is a polyphenol with previously described antioxidant and neuroprotective properties. The aim of this study was to evaluate the effects of TA on lipopolysaccharide (LPS)-induced depressive-like behavior, as well as oxidative stress parameters and TNF-α levels in the brains of mice. Animals were pretreated once daily, with TA (30 or 60 mg/kg), fluoxetine (20 mg/kg) or vehicle for 7 days. On the 7th day, the animals received a single injection of LPS (830 µg/kg). After 24 h, open field, forced swimming, tail suspension, and splash tests were conducted. The endotoxin induced depressive-like behavior in these mice and this was attenuated by TA. In the cerebral cortex, hippocampus, and striatum, LPS increased lipid peroxidation and reactive oxygen species production, and this was also prevented by TA administration. TA treatment also prevented a decrease in catalase activity within the striatum. Further, LPS administration caused increased levels of TNF-α in all brain structures, and this was prevented in the cortex by TA treatment. In conclusion, TA shows many neuroprotective properties, with demonstrated antioxidant, anti-inflammatory and antidepressant effects in this animal model of acute depressive-like behavior. Therefore, this compound could provide an alternative therapeutic approach for the treatment of depression.

Insights into serotonergic and antioxidant mechanisms involved in antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran in mice.

Monoaminergic and oxidative dysfunctions have been reported to play a role in depression. The present study investigated the antioxidant potential as well as the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in male Swiss mice. Time and dose-response curves were analyzed with the forced swim (FST) and tail suspension (TST) tests, in which SeBZF1 elicited antidepressant-like effects. Serotonergic mechanisms were investigated in the TST. The pre-administration of WAY100635 (selective 5-HT1A receptor antagonist, 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/2C receptor antagonist, 1 mg/kg, intraperitoneal route, i.p.), and chlorophenylalaninemethyl ester (p-CPA) (selective tryptophan hydroxylase inhibitor, 100 mg/kg, i.p., for 4 days), but not of ondansetron (selective 5-HT3 receptor antagonist, 1 mg/kg, i.p.), abolished the antidepressant-like action of SeBZF1 (50 mg/kg, intragastric route, i.g.). Co-administration of sub-effective doses of SeBZF1 (1 mg/kg, i.g.) and fluoxetine (5 mg/kg, i.p., selective serotonin reuptake inhibitor) was effective in producing anti-immobility effects in the TST, revealing a synergistic effect. Besides, p-CPA induced hippocampal oxidative stress, characterized by a reduction of total thiols and lipoperoxidation, which was reversed by SeBZF1 (50 mg/kg). The in vitro screening of the antioxidant action of SeBZF1 in brain tissue reinforced these results. Lastly, SeBZF1 did not cause systemic toxicity at a high dose (300 mg/kg). In summary, the present study demonstrated that SeBZF1 exerted antidepressant-like action in male mice which appears to be mediated by the serotonergic system. Moreover, SeBZF1 elicited in vitro antioxidant action in brain tissue, attenuated the hippocampal oxidative damage induced by 5-HT depletion in mice and showed no toxic signs.

Characterization of macrophage phenotype, redox, and purinergic response upon chronic treatment with methionine and methionine sulfoxide in mice.

Hypermethioninemia is a disorder characterized by high plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO). Studies have reported associated inflammatory complications, but the mechanisms involved in the pathophysiology of hypermethioninemia are still uncertain. The present study aims to evaluate the effect of chronic administration of Met and/or MetO on phenotypic characteristics of macrophages, in addition to oxidative stress, purinergic system, and inflammatory mediators in macrophages. In this study, Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. The results revealed that Met and/or MetO induce an M1/classical activation phenotype associated with increased levels of tumor necrosis factor alpha and nitrite, and reduced arginase activity. It was also found that Met and/or MetO alter the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of thiol and reactive oxygen species in macrophages. The chronic administration of Met and/or MetO also promotes alteration in the hydrolysis of ATP and ADP, as indicated by the increased activity of ectonucleotidases. These results demonstrate that chronic administration of Met and/or MetO promotes activated pro-inflammatory profile by inducing M1/classical macrophage polarization. Thus, the changes in redox status and purinergic system upon chronic Met and/or MetO exposure may contribute towards better understanding of the alterations consistent with hypermethioninemic patients.